HCV: La realtà clinica

HCV: La realtà clinica

MALATTIE DI FEGATO 5 causa di morte al mondo (dopo patologie cardio e cerebro-vascolari, polmonari, oncologiche) HBV ETOH HCV AFLATOSSINA NAFLD WHO - UK NATIONAL STATISTICS

HCV: Epidemiologia e distribuzione dei Genotipi EASL update on hepatitis C, November 2014

EPIDEMIOLOGIA DELL INFEZIONE DA HCV TECHNICAL REPORT Hepatitis B and C in the EU neighbourhood: prevalence, burden of disease and screening policies September 2010

PREVALENZA HCV PER CLASSI DI ETÀ E PROVENIENZA GEOGRAFICA % 35 30 Sud 25 20 Centro 15 10 Nord 5 0 < 30 30-39 40-49 50-59 > 60 Maio R et al, J Hepatol 2000 Di Stefano G et al, J Med Virol 2002

HCV: GRADIENTE NORD-SUD Prevalenza della positività di HCV-RNA nelle diverse regioni italiane in relazione all età Brescia Vallecamonica - Sebino AISF FIRE - Libro Bianco dell Epatologia Italiana - EPIDEMIOLOGIA DELLE EPATOPATIE ACUTE E CRONICHE IN ITALIA. A cura della Commissione Epidemiologia dell Associazione Italiana per lo Studio del Fegato (A.I.S.F.) Febbraio 2007. - Zani et al DLD 2011.

HCV: PRINCIPALE CAUSA DI EPATOPATIA CRONICA IN ITALIA ALTRO 15,6% HBsAg + 9,9% AlCOL+HCV 12,1% ALCOL 6,2% HCV: 1.5-2 milioni di infetti in Italia HCV + 56,6%

THE LIVER MATCH STUDY Main Indications For Liver Transplantation in Italy Total number of first liver transplants = 1240 50 % dei Trapianti in pazienti con infezione da HCV Re-OLTx N. = 100 (7.5%) * Autoimmune 0.35%; liver rupture 0.15% Angelico et al. Dig Liv Dis; 2011, mod.

STORIA NATURALE HCV Infezione protettiva Immunità T-cellulare 10% Infezione 10% 75% 5% Infezione subclinica ALT normali Epatite cronica Epatite acuta 1-4% Cirrosi 15-25% Guarigione HCC Scompenso

STORIA NATURALE HCV Infezione 75% Epatite cronica 5-30 anni 15-25% HCC 1-4% Cirrosi >30% Scompenso

PROGRESSIONE HCV: Ruolo Cofattori FATTORI LEGATI ALL OSPITE ALTRI FATTORI Età avanzata Sesso: M>F Stato immunitario FATTORI LEGATI AL VIRUS Alcol Farmaci Steatosi Coinfezioni HCV, HIV Carica virale Genotipo Più rapida progressione epatopatia HCV relata Liaw, Liver Int 2006

PROGRESSIONE HCV Picco di incidenza infezione HCV negli anni 50-70 prima che fossero disponibili test per HCV La maggior parte dei pazienti con epatite cronica C si trova attualmente nella 5-7 decade di vita Quando raggiungeranno 60-70 anni probabile patologia clinicamente manifesta

Manifestazioni extraepatiche dell infezione da HCV A: Association defined on the basis of: 1. High prevalence 2. Pathogenesis Mixed cryoglobulinemia, cryoglobulinemic nephropathies B: Association defined on the basis of higher prevalences than in controls B-cell non-hodgkin s lymphoma Monoclonal gammopathies Porphyria cutanea tarda Lichen planus C: Associations to be confirmed/characterized Autoimmune thyroiditis Thyroid cancer Sicca syndrome Alveolitis-Lung fibrosis Diabetes mellitus Non-cryoglobulinemic nephropathies D: Anecdotal observations Psoriasis, Vitiligo Peripheral/central neuropathies Polyarthritis Rheumatoid arthritis Polyartheritis nodosa Bechet s syndrome Poly/dermatomyositis, Fibromyalgia Chronic urticaria/pruritus Kaposi s pseudo-sarcoma Cardiopathies/cardiomyopathies Mooren corneal ulcer Erectile dysfunctions

CONSEGUENZE CLINICHE Attualmente l infezione da HCV è responsabile di: 12000-16000 decessi/anno negli USA 8000-12000 decessi/anno in Italia Negli USA, sulla base di proiezioni epidemiologiche si stima che, nelle prossime 2 decadi: aumento ospedalizzazioni per epatopatia HCVrelata di circa 25-30% per anno aumenterà di 2-4 volte della mortalità per HCV McHutchinson JG et al, Am J Manag Care 2005

MORTALITÀ DA MALATTIA DI FEGATO 2010 morti/100.000 abitanti 60 50 40 30 20 10 0 15 25 35 45 55 65 75 85 95 età Maschi Femmine

PROIEZIONE DELLE PATOLOGIE EPATICHE HCV-RELATE NEI PROSSIMI DECENNI prevalenza (x 1000) 3500 3000 2500 2000 1500 1000 500 0 Epatite cronica HCV 2000 2010 2020 2030 2040 Cirrosi HCV-relata Nei prossimi 40 anni il numero totale di pazienti con epatite cronica C diminuirà gradualmente Il numero dei casi di cirrosi crescerà più del 50% per il 2010 e successivamente subirà un plateau prevalenza (x 1000) 1000 900 800 700 600 500 400 300 200 100 0 2000 2010 2020 2030 2040 In particolare, la percentuale di epatiti croniche HCVrelate che evolverà in cirrosi aumenterà del 25% nel 2010, del 32% nel 2020, del 36% nel 2030, del 38% nel 2040 Davis GL et al. Liver Transpl, 2003

PROIEZIONE DELLE PATOLOGIE EPATICHE HCV-RELATE NEI PROSSIMI DECENNI Cirrosi HCV-relata scompensata prevalenza (x 1000) prevalenza (x 1000) 160 140 120 100 80 60 40 20 0 16 14 12 10 8 6 4 2 0 2000 2010 2020 2030 2040 HCC in pazienti HCV+ 2000 2010 2020 2030 2040 Parallelamente ad un aumento progressivo dei pazienti affetti da cirrosi epatica si assisterà a: Incremento casi di scompenso epatico Incremento di HCC comparsa Davis GL et al, Liver Transpl 2003

MORTALITÀ PER TUMORE AL FEGATO IN EUROPA CORRELATA ALLA POSITIVITÀ PER MARCATORI HCV E HBV TECHNICAL REPORT Hepatitis B and C in the EU neighbourhood: prevalence, burden of disease and screening policies September 2010

HCV THERAPY Standard Interferon Interferon + Ribavirin 1991 1998 2001 Peginterferon/ Ribavirin GT1 GT2/3 Boceprevir or Telaprevir + P/R Simeprevir or Sofosbuvir + P/R 2005 2011 2014 2014 Sofosbuvir + Ribavirin dic. 14 19

RISPOSTA ALLA TERAPIA ANTI-HCV (fino al 2013) RISPOSTA VIROLOGICA SOSTENUTA (SVR) HCV 1 HCV 2/3 HCV 4 HCV 5 HCV 6-9 40-70% 75-85% 40-68% 58-71% 40-62% Terapia basata su interferone/ribavirina e nel G1 anche su DAA di I generazione

HCV LIFE CYCLE AND NOVEL DAA TARGETS NS5A inhibitors Block replication complex formation, assembly Receptor binding and endocytosis Transport and release Translation and polyprotein processing Fusion and uncoating (+) RNA LD ER lumen LD Virion assembly NS3/4 protease inhibitors ER lumen Membranous web LD RNA replication NS5B polymerase RNA inhibitors replication Nucleoside/nucleotide Nonnucleoside Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000.

Key Negative Features of 1 st generation DAAs Pill Burden Low genetic barrier to resistance Subpar efficacy in some patients Poor Tolerability

HCV RNA Emergence of Pre-existing Resistant Variants During Treatment with DAA Baseline HCV RNA Drug Potency Viral breakthrough Resistance Barrier X X X X X X X X X Before Treatment Time on Treatment with DAA Alone Resistant virus Sensitive virus

SVR (%) SVR by Fibrosis Stage and Prior Response to Peg-IFN/RBV 100 Prior relapsers Prior partial responders Prior null responders 86% 85% 80 72% 60 40 20 42% 41% 25% 0 144/167 101/119 34/47 21/50 24/59 22/88 F0/F2 F3/F4 F0/F2 F3/F4 F0/F2 F3/F4 Zeuzem S, et al. NEJM 2011

CUPIC: SVR12 and the risk of occurrence of severe complications Platelets count Platelets count 100,000/mm 3 >100,000/mm 3 Albumin <35 g/l N Complications, n (%) SVR12, n (%) 37 19 (51.4%) 8 (21.6%) 31 5 (16.1%) 8 (29.0%) Albumin 35 g/l N Complications, n (%) SVR12, n (%) 74 9 (12.2%) 25 (33.8%) 306 19 (6.2%) 165 (53.9%) Hézode C, et al. Gastroenterology. 2014 Jul;147(1):132-142

Percentage of patients (%) Anaemia & Rash Adverse Events: The Telaprevir EAP Grade 1: Hb 10.0 10.9 g/dl; decrease 2.5 3.4 g/dl Grade 2: Hb 9.0 9.9 g/dl; decrease 3.5 4.4 g/dl Grade 3: Hb 7.0 8.9 g/dl; decrease >4.5 g/dl Grade 4: Hb <7.0 g/dl 59% 42% Colombo M et al, Gut 2014; 63(7):1150-8

2 nd Generation DAAs 2nd Wave Protease inhibitors Simeprevir (SMV) NS5B Polymerase inhibitors Sofosbuvir (SOF) NS5A Inhibitors Daclatasvir(DCV)

Key Features of 2nd generation DAAs SMV SOF DCV Pill Burden + + + Tolerability +/- + + Genetic barrier to resistance Efficacy in difficult to cure patients +/- + +/- + + +

1. ABT 450 (with ritonavir: ABT 450r): protease inhibitor 2. Ombitasvir (ABT 267): NS5A inhibitor 3. Dasabuvir (ABT 333): nonnucleoside polymerase inhibitor 4. Sofosbuvir: nucleotide polymerase inhibitor 5. Ledipasvir: NS5A inhibitor 6. Daclatasvir: protease inhibitor 7. Simeprevir: protease inhibitor Single tablet Coformulation once daily Twice daily Single tablet Coformulation once daily

Gennaio/maggio 2014 1. Daclatasvir plus Sofosbuvir for HCV Infection 2. Treatment of HCV with ABT-450/r Ombitasvir and Dasabuvir with Ribavirin 3. ABT-450/r Ombitasvir and Dasabuvir with Ribavirin for Hepatitis C with Cirrhosis 4. Ledipasvir and Sofosbuvir for Untreated HCV Genotype 1 Infection 5. Ledipasvir and Sofosbuvir for Previously Treated HCV Genotype 1 Infection 6. Ledipasvir and Sofosbuvir for 8 or 12 Weeks for Chronic HCV without Cirrhosis

24 aprile 2014 SAPPHIRE-I (funded by Abbvie) dic. 14 31

SAPPHIRE-I Phase 3 trial Multicenter, Randomized, Double-blind, Placebocontrolled trial Previously untreated patients with HCV genotype 1 infection and no cirrhosis Interferon-free regimen, all oral antiviral therapy dic. 14 32

SAPPHIRE-I: results dic. 14 33

Virologic Failure With 3 DAAs + RBV in Treatment-Naive Pts SAPPHIRE-I Virologic failure occurred in 7 patients with GT1a and 1 patient with GT1b Relapses occurred at posttreatment Wk 2 (n = 3), Wk 8 (n = 3), and Wk 12 (n = 1) Emergent resistance-associated variants uncommon: 8/473 pts (1.7%) GT1a: D168V (6/7) in NS3; M28T (2/7) and Q30R (3/7) in NS5A; and S556G (3/7) in NS5B GT1b: Y56H + D168V in NS3; L31M + Y93H in NS5A; and S556G in NS5B dic. 14 34

ADVERSE EVENTS SAPPHIRE-I dic. 14 35

11 aprile 2014 TURQUOISE II (sponsored by Abbvie) dic. 14 36

TURQUOISE II Open-label Phase 3 trial Involving Inclusion criteria: GT1 Compensated cirrhosis (Child-Pugh A) DAA naïve (previously untreated and previously treated) HCV RNA level of more than 10,000 IU per milliliter Radiographic ascites and varices permitted, serum albumin 2.8 g/dl, total bilirubin < 3 mg/dl, serum AFP 100 ng/ml, INR 2.3, platelets 60,000 cells/ml dic. 14 37

TURQUOISE II: results Sustained Virologic Response at Post-Treatment Week 12 in Each Treatment Group, Overall and According to Subgroups dic. 14 38

SVR12 (%) 100 92.292.9 GT1a 93.3100 100 100 92.9 80.0 TURQUOISE II: results 12 wks 24 wks 100 100 100 GT1b 100 100 85.7100 100 100 80 80 60 60 40 40 20 20 0 59/ 64 52/ 56 Naive 14/ 15 13/ 13 11/ 11 10/ 10 Relapse Partial Response Null Response Naive Poordad F, et al. EASL 2014. Abstract O163. Reproduced with permission. 40/ 50 39/ 42 Relapse Partial Response Null Response Virologic failure in 17/380 pts (4.5%); relapse more frequent with 12-wk vs 24-wk treatment (12 vs 1 pt), 7/12 relapsers by posttreatment Wk 12 were GT1a null responders 0 22/ 22 18/ 18 25/ 25 20/ 20 6/7 3/3 14/ 10/ 14 10 dic. 14 39

TURQUOISE II: adverse events Titolo della Presentazione dic. 14 40

15 maggio 2014 Afdhal N et al ION-1: sponsored by Gilead dic. 14 41

ION-1 Phase 3 Multicenter, Randomized, Open-label study Previously untreated patients with chronic HCV genotype 1 infection No upper limits for age or body-mass index Patients with cirrhosis could account for approximately 20% of the study population dic. 14 42

SVR12 (%) ION-1: results 100 99 94 97 100 98 94 99 100 80 60 No cirrhosis Cirrhosis 40 20 0 179/ 180 32/ 34 SOF/LDV 178/ 184 33/ 33 SOF/LDV + RBV 181/ 184 SOF/LDV 31/ 33 179/ 181 36/ 36 SOF/LDV + RBV 12 Wks 24 Wks SVR12 rates did not differ by GT1a vs GT1b in any treatment arm Virologic failure: 1 breakthrough in 24-wk SOF/LDV; 2 relapses (1 in 12-wk SOF/LDV, 1 in 24-wk SOF/LDV) 16% of patients had NS5A resistance-associated variants at baseline; 96% of these achieved SVR12 Mangia A, et al. EASL 2014. Abstract O164. Reproduced with permission. Afdhal N, et al. N Engl J Med. 2014;[Epub ahead of print]. dic. 14 43

ION-1

17 aprile 2014 Afdhal N et al ION-2: sponsored by Gilead dic. 14 45

Phase 3 ION-2 Randomized, Open-label study Patients infected with HCV genotype 1 who had not had a sustained virologic response after treatment with peginterferon and ribavirin, with or without a protease inhibitor (NS3/4A protease inhibitor) (experienced) Patients who had discontinued prior treatment owing to an adverse event were not eligible 20% of participants had cirrhosis, 41% to 46% were previous nonresponders, and 46% to 61% had failed a PI dic. 14 46

SVR12 (%) 100 ION-2 93 94 96 97 100 98 98 100 80 60 40 Failure on pegifn/rbv Failure on PI 20 0 40/ 43 62/ 66 LDV/SOF 45/ 47 62/ 64 LDV/SOF + RBV 58/ 58 49/ 50 LDV/SOF 12 Wks 24 Wks 58/ 59 51/ 51 LDV/SOF + RBV Virologic failure: 1 breakthrough in 24-wk SOF/LDV/RBV due to nonadherence; 11 relapses (7 in 12- wk SOF/LDV, 4 in 12-wk SOF/LDV/RBV) 14% of patients had NS5A resistance-associated variants at baseline; 89% of these achieved SVR12 Afdhal N, et al. EASL 2014. Abstract O109. Reproduced with permission. Afdhal N, et al. N Engl. J Med. 2014;370:1483-1493. dic. 14 47

ION-2 Titolo della Presentazione dic. 14 48

15 magio 2014 Kowdley KV et al ION-3 dic. 14 49

ION-3 Multicenter, Randomized, open-label trial Phase 3 18 years of age or older Chronic HCV genotype 1 infection without cirrhosis Naïve to treatment for HCV infection HCV RNA level of at least 104 IU per milliliter at the time of screening, alanine and aspartate aminotransferase levels of no more than 10 times the upper limit of the normal range, a platelet count of more than 90,000 per cubic millimeter, and a hemoglobin level of at least 11 g per deciliter (in women) or at least 12 g per deciliter (in men). dic. 14 50

ION-3 Wk 8 Wk 12 Treatment-naive, noncirrhotic pts with HCV GT1 (N = 647) SOF/LDV (n = 215) SOF/LDV + RBV (n = 216) SOF/LDV (n = 216) Sofosbuvir/ledipasvir 400/90 mg FDC tablet once daily; weight-based RBV 1000-1200 mg/day Patients were randomly assigned in a 1:1:1 ratio Randomization was stratified according to HCV genotype (1a or 1b) dic. 14 51

SVR12 (%) ION-3 P =.52 P =.70 P =.30 100 94 93 95 80 60 40 20 0 202/215 201/216 206/216 SOF/LDV SOF/LDV + RBV SOF/LDV 8 Wks 12 Wks SVR12 rates did not differ by GT1a vs GT1b in any treatment arm Virologic failure: 23 relapses (11 in 8-wk SOF/LDV, 9 in 8-wk SOF/LDV/RBV, 3 in 12-wk SOF/LDV)

ION-3

Pretransplant Sofosbuvir + Ribavirin Patient population - DDLT candidates with HCV and HCC meeting MILAN criteria - MELD exception for HCC - CPT 7 Enrollment at 16 sites - 8 UNOS regions - 2 international sites 61 patients enrolled Original protocol: until LT or up to 24 weeks of treatment - Amendment: extend treatment duration to 48 weeks or LT Curry MP et al, Gastroenterology in press

Results: Post-Transplant Virologic Response *3 subjects were >LLOQ at transplant. 1 subject has not reached ptvr12, 1 subject LTFU at Week 8 post transplant. Curry MP et al, Gastroenterology in press

SVR and The Natural History of Hepatitis C Variceal Bleeding Acute Hepatitis Chronic Hepatitis Cirrhosis Liver decompensation HCC Modified by Lauer and Walker NEJM 2001;345:41-52

SVR and The Natural History of Hepatitis C HCC Unproved and Unprovable with IFN! IFN contraindicated in decompensated cirrhosis Chronic Hepatitis Cirrhosis and after variceal bleeding Acute Hepatitis Liver decompensation Low SVR rates in patients with HCC Variceal Bleeding Modified by Lauer and Walker NEJM 2001;345:41-52

SOF+RBV for Treatment of Chronic HCV with Cirrhosis and Portal HTN ± Decompensation: Week 24 Interim Results Randomized, open-label, safety and efficacy study of SOF+RBV for 48 weeks compared to observation for 6 months in patients with HCV cirrhosis and portal HTN (CTP 5 9) Arm 1 n=25 Arm 2 n=25 Wk 0 SOF 400 mg + RBV 1000 1200 mg Observation Preliminary results Wk 24 Wk 48 SOF 400 mg + RBV 1000 1200 mg Afdhal N, EASL, 2014, O68 Wk 72 SVR12 Wk 96 SVR12 SOF + RBV n=25 Observation n=25 Male, n (%) 18 (72) 20 (80) Median age, y (range) 56 (43 69) 55 (44 69) BMI 30 kg/m 2, n (%) 8 (32) 7 (28) Mean HCV RNA, log 10 IU/mL (range) GT, n (%) 6.1 (4.4 7.0) 6.1 (3.8 6.9) 1a 10 (40) 9 (36) 1b 9 (36) 6 (24) 2 2 (8) 1 (4) 3 2 (8) 8 (32) 4 2 (8) 1 (4) IL28B non-cc, n (%) 22 (88) 18 (72) Prior HCV treatment, n (%) 17 (68) 23 (92) Mean HVPG mmhg, n (range) 16.9 (9 29) 16.2 (7 27) HVPG >12 mmhg, n (%) 19 (76) 20 (80)

Difficult-to-Treat Patients: Decompensated Cirrhosis and Portal Hypertension Afdhal N et al, EASL OC #68

Difficult-to-Treat Patients: Decompensated Cirrhosis and Portal Hypertension (II) MELD Changes During Treatment/Observation Afdhal N et al, EASL OC #68

The Risk of Treating Patients with Too Advanced Liver Disease Pellicelli A et al, Digestive and Liver Disease 2014; 46: 923-927

EPATITE HCV: CONCLUSIONI Le malattie epatiche croniche rappresentano un serio problema medico e sociale L infezione da virus HCV è un grande problema sanitario specie nei paesi in via di sviluppo L epatopatia conseguente all infezione e un problema che colpisce il 2-7% della popolazione italiana In conseguenza dell effetto coorte di HCV, le previsioni relative ai prossimi 40 anni identificano nella popolazione geriatrica la massima prevalenza di epatopatici cronici

EPATITE HCV: CONCLUSIONI Nell anziano la probabilità che si verifichi un evento in grado di determinare uno scompenso epatico è maggiore rispetto al giovane Dopo il primo di questi eventi la sopravvivenza si riduce drasticamente Prevenzione complicanze Stretto follow-up Studi efficacia/tollerabilità terapia antivirale negli anziani Criteri di inserimento in lista OLT meno restrittivi

EPATITE HCV: CONCLUSIONI L efficacia delle nuove terapie antivirali per il virus C cambiera l approccio clinico e la tipologia di pazienti trattabili Costi Willingness to pay Futilita

Treatment Options PegIFNa + ribavirin + sofosbuvir 12 weeks PegIFNa + ribavirin + simeprevir 12 weeks +RGT 12/36 PegIFNa + ribavirin + daclatasvir 12 weeks +RGT 12 Sofosbuvir + ribavirin 12-24 weeks Sofosbuvir + simeprevir (± ribavirin) 12 weeks Sofosbuvir + daclatasvir (± ribavirin) 12-24 weeks

The (Probable) Italian Scenario 2nd Generation DAAs available in 2015 for: Liver Transplant Patients Patients on the OLT waiting list Decompensated Patients Patients with cirrhosis

INFEZIONE CRONICA VIRALE: SCENARIO ATTUALE HCV HBV HIV STIME PORTATORI VIRUS 1.600.000 600.000 140.000 STIME CIRROSI / AIDS 230.000 100.000 22.000 DECESSI / ANNO > 11.000 1.500 937 INSERITA in PSN NO NO SI LEGGE AD HOC CON FINANZIAMENTI NO NO SI NUMERO VERDE NO NO SI CAMPAGNE DI SENSIBILIZZAZIONE NO NO SI Dati ISS